Microtubule stabilising agents and ionising radiation: Multiple exploitable mechanisms for combined treatment

Abstract

Combined radiochemotherapy treatment modalities are in use for many indications and therefore of high interest. Even though a combined modality in clinical use is often driven by prag-matic aspects, mechanistic preclinical-based concepts of interaction are of importance in order to translate and implement an optimal combination and scheduling of two modalities into the clinics. The use of microtubule stabilizing agents is a promising strategy for anti-cancer therapy as a part of combined treatment modality with ionizing radiation. Traditionally, microtubule targeting agents are classified as cytotoxic chemotherapeutics and are mostly used in a maxi-mally tolerated dose regimen. Apart from direct cytotoxicity and similar to mechanisms of mo-lecular targeting agents, microtubule stabilizing agents interfere with multiple cellular process-es, which can be exploited as part of combined treatment modalities. Recent preclinical investi-gations on the combination of ionizing radiation and microtubule stabilizing agents reveal new mechanistic interactions on the cellular and tumor level and elucidate the supra-additive tumor response observed particularly in vivo. The major focus on the mechanism of interaction was primarily based on radiosensitization due to cell cycle arrest in the most radiosensitive G2/M-phase of the cell cycle. However, other mechanisms of interaction such as reoxygenation and direct as well as indirect endothelial damage have also been identified. In this review we sum-marize and allocate additive and synergistic effects induced by the combined treatment of clini-cally relevant microtubule stabilizing agents and ionizing radiation along a described radiobio-logical framework encompassing distinct mechanisms relevant for exploiting the combination of drugs and ionizing radiation. primarily based on radiosensitization due to cell cycle arrest in the most radiosensitive G2/Mphase of the cell cycle. However, other mechanisms of interaction such as reoxygenation and direct as well as indirect endothelial damage have also been identified. In this review we summarize and allocate additive and synergistic effects induced by the combined treatment of clinically relevant microtubule stabilizing agents and ionizing radiation along a described radiobiological framework encompassing distinct mechanisms relevant for exploiting the combination of drugs and ionizing radiation.

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